(a) Field of the Invention
The invention relates to 6-substituted pyrazolo[3,4-d]-pyrimidin-4-ones, to pharmaceutical compositions containing them and to methods for effecting c-GMP-phosphodiesterase inhibition and for treating heart failure and/or hypertension.
(b) Information Disclosure Statement
Schmidt et al., U.S. Pat. No. 3,165,520, issued Jan. 12, 1965, disclose as coronary dilating agents pyrazolo-[3,4-d]pyrimidines of general formula: ##STR1## wherein: R.sup.1 represents a hydrogen atom or an alkyl, hydroxyalkyl, halogen-alkyl or oxa-alkyl radical or a cycloalkyl, cycloalkyl-alkyl, aralkyl or heterocyclylalkyl radical or an at most binuclear aryl or heterocyclic radical;
R.sup.3 represents a hydrogen atom or a lower-alkyl radical; PA1 R.sup.5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heterocyclic-aliphatic radical; and PA1 R.sup.6 represents an aliphatic radical or an aralkyl or heterocyclyl-alkyl radical which may be substituted. PA1 R.sup.3 stands for hydrogen, or in the second place, for a lower-alkyl radical; and PA1 R.sup.6 represents a possibly substituted aralkyl or heterocyclylalkyl radical. PA1 R.sup.1 represents a hydrogen atom, a lower-alkyl radical which is unsubstituted or substituted by a hydroxy group or a lower-alkoxy group, or a cyclopentyl or cyclohexyl radical or a phenyl or phenyl lower-alkyl radical; PA1 R.sup.3 represents a hydrogen atom or a lower-alkyl radical; and PA1 R.sup.6 stands for a substituted or unsubstituted phenyl lower-alkyl radical. PA1 R.sup.1 stands for a hydrogen atom, a lower-alkoxy-lower-alkyl radical or a hydroxy-lower-alkyl radical, a cyclopentyl or cyclohexyl radical or a phenyl or phenyl-lower-alkyl radical which may be substituted; PA1 R.sup.3 has the meanings given above; and PA1 R.sup.6 stands for a phenyl radical which may be substituted. Specifically disclosed is 1-isopropyl-4-hydroxy-6-phenylpyrazolo-[3,4-d]pyrimidine. PA1 n is 0-4; and PA1 Ar is R.sub.2 : ##STR6## or 2, 3 or 4-pyridyl wherein X, Y and Z are independently (1) hydrogen; (2) lower-alkyl of from one to six carbons, inclusive; (3) halogen; (4) hydroxyl; (5) lower-alkoxy of from one to six carbons, inclusive; (6) nitro; (7) amino; (8) NR'R" wherein R' and R" are each independently (a) hydrogen or (b) lower-alkyl of from one to six carbons, inclusive, optionally substituted by (i) amino, (ii) morpholino, or (iii) cycloalkyl of from five to seven carbons, inclusive, (9) sulfonyl or (10) --SO2 NR'R" wherein R' and R" are as defined above. PA1 R.sup.2 is hydrogen or lower-alkyl; and PA1 R.sup.3 is hydrogen, lower-alkyl, halogen, or trifluoromethyl. Specifically disclosed are 1,3-dimethyl-6-styryl-pyrazolo[3,4-d]pyrimidine, 1-cyclopentyl-6-(2-chlorostyryl)pyrazolo[3,4-d]pyrimidine, 1-cyclohexyl-3-methyl-6-(styryl)pyrazolo[3,4-d]pyrimidine and 1,3-diethyl-6-(4-chlorostyryl)pyrazolo[3,4-d]pyrimidine. The compounds are said to be useful as antimicrobial agents and to possess antiinflammatory and membrane stabilizing properties. PA1 R.sup.3 is methyl, ethyl, or phenylmethyl; PA1 X is --CH.sub.2 --, --O--, or --NH--; and PA1 R.sup.6 is phenyl (or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, hydroxy, halogen, carboxylower-alkoxy, 4-morpholinyl-lower-alkoxy, 5-tetrazolyl-lower-alkoxy, dilower-alkylamino, trifluoromethyl, nitro, amino, lower-alkylsulfonylamino, dilower-alkylamino-lower-alkylphenyl carbonyloxy, and 1-imidazolyl); or when X is --CH.sub.2 --, R.sup.6 is additionally 2-,3-, or 4-pyridinyl, 1-pyrrolyl, 1-benzimidazolyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1,2,3,4-tetrahydro-1-quinolinyl, hydroxy, 1-imidazolyl, 1-lower-alkyl-2-,3-,4-, or 5-pyrrolyl, 1-pyrazolyl, 3-,4-, or 5-isoxazolyl(or 3-,4-, or 5-isoxazolyl substituted on any available carbon atom thereof by lower-alkyl), 2-thienyl, or 3-thienyl; or a pharmaceutically acceptable acid-addition salt and/or hydrate thereof. PA1 R.sup.1, R.sup.3 and X are as defined hereinabove; and PA1 R.sup.6 is phenyl (or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, hydroxy, carboxylower-alkoxy, 4-morpholinyl-lower-alkoxy, 5-tetrazolyl-lower-alkoxy, dilower-alkylamino, trifluoromethyl, nitro, amino, lower-alkylsulfonylamino, dilower-alkylamino-lower-alkylphenyl carbonyloxy, and 1-imidazolyl); or when X is --CH.sub.2 --, R.sup.6 is additionally 2-,3-, or 4-pyridinyl, 1-pyrrolyl, 1-benzimidazolyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1,2,3,4-tetrahydro-1-quinolinyl, hydroxy, 1-imidazolyl, 1-lower-alkyl-2-pyrrolyl, 1-pyrazolyl, 4-isoxazolyl substituted on any available carbon atom thereof by lower-alkyl, 2-thienyl, or 3-thienyl. PA1 R.sup.1, R.sup.3 and X are as defined hereinabove; and PA1 R.sup.6 is phenyl (or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of methoxy, hydroxy, carboxymethoxy, 2-(4-morpholinyl)ethoxy, 1-(5-tetrazolyl)methoxy, dimethylamino, trifluoromethyl, nitro, amino, methylsulfonylamino, diethy-laminomethylphenylcarbonyloxy, and 1-imidazolyl); or when X is --CH.sub.2 --, R.sup.6 is additionally 2-,3-, or 4-pyridinyl, 1-pyrrolyl, 1-benzimidazolyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1,2,3,4-tetrahydro-1-quinolinyl, hydroxy, 1-imidazolyl, 1-methyl-2-pyrrolyl, 1-pyrazolyl, 3,5-dimethyl-4-isoxazolyl, 2-thienyl, or 3-thienyl. PA1 1-cyclopentyl-3-ethyl-6-(4-methoxyphenylmethyl)pyrazolo [3,4-d]pyrimindin-4-one, PA1 1-cyclopentyl-3-ethyl-6-(4-hydroxyphenylmethyl)pyrazolo [3,4-d]pyrimindin-4-one, PA1 1-cyclopentyl-3-ethyl-6-(phenylmethyl)pyrazolo[3,4-d]pyrimindin-4-one, and PA1 1-cyclopentyl-3-ethyl-6-(4-aminophenylmethyl)pyrazolo [3,4-d]pyrimindin-4-one.
The patent more specifically discloses as especially valuable the compounds in which R.sup.1 represents a hydrogen atom or a lower-alkyl radical or a cycloalkyl radical, a hydroxy-lower-alkyl radical or halogen-lower-alkyl radical, an oxa-lower-alkyl, or an aryl radical which may be unsubstituted or mono-, di-, or tri-substituted by halogen, alkoxy, alkyl, methylenedioxy, trifluoromethyl, nitro, amino, or a pyridyl radical; R.sup.3 represents a hydrogen atom or a lower-alkyl radical; R.sup.5 represents a lower-alkyl radical or a lower-alkylamino radical; and R.sup.6 represents a lower-alkyl radical or an aralkyl radical.
Further disclosed are a series of 1-R.sup.1 -3-R.sup.3 -4-hydroxy-6-R.sup.6 -pyrazolo[3,4-d]pyrimidines which are said to be useful as intermediates in the synthesis of final products. Among the intermediates specifically disclosed are 1-cyclopentyl-4-hydroxy-6-benzyl-pyrazolo[3,4-d]pyrimidine and 1-isopropyl-4-hydroxy-6-m-methoxybenzylpyrazolo[3,4-d]pyrimidine.
Schmidt et al., U.S. Pat. No. 3,211,731, issued Oct. 12, 1965, disclose as coronary dilating agents pyrazolo-[3,4-d]pyrimidines of general formula: ##STR2## wherein: R.sup.1 represents hydrogen, an alkyl, hydroxy-alkyl, halogen-alkyl or oxa-alkyl radical, a cyclo-alkyl, cyclo-alkylalkyl, aralkyl, heterocyclyl-alkyl radical or an at most binuclear aryl or heterocyclic radical;
The patent more specifically discloses as especially valuable the compounds in which R.sup.1 represents a hydrogen atom or a lower-alkyl group, cycloalkyl, hydroxy-lower-alkyl, halogen-lower-alkyl, oxa-lower-alkyl, or an aryl; R.sup.3 represents a hydrogen atom or lower-alkyl and R.sup.6 a substituted or unsubstituted aralkyl. Among the compounds specifically disclosed are 1-isopropyl-4-hydroxy-6-(3'-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidine, 1-cyclopentyl-4-hydroxy-6-benzylpyrazolo[3,4-d]pyrimidine, 1-iso-propyl-4-hydroxy-6-(.beta.-phenylethyl)pyrazolo[3,4-d]pyrimidine, and 1-isopropyl-4-hydroxy-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidine.
Schmidt et al., U.S. Pat. No. 3,211,732, issued Oct. 12, 1965, disclose, as intermediates, 1-R.sup.1 -3-R.sup.3 -6-R.sup.6 -4-hydroxy-pyrazolo[3,4-d]pyrimidines wherein:
Specifically disclosed is 1-isopropyl-4-hydroxy-6-benzylpyrazolo[3,4-d]pyrimidine.
Also disclosed, as intermediates, are 1-R.sup.1 -3-R.sup.3 -6-R.sup.6 -4-hydroxypyrazolo[3,4-d]pyrimidines wherein:
Breuer et al., U.S. Pat. No. 3,732,225, issued May 8, 1973, disclose as hypoglycemic agents and anti-inflammatory agents pyrazolo[3,4-d]pyrimidines of formula: ##STR3## wherein: R is hydrogen or lower-alkyl; R.sup.1 is lower-alkyl, cycloalkyl, phenyl or substituted phenyl; R.sup.2 is phenyl, substituted phenyl or cycloalkyl; and R.sup.3 is hydrogen, lower-alkyl, cycloalkyl, phenyl or substituted phenyl. Specifically disclosed are 1-methyl-6-phenyl and 1-methyl-6-(4-chlorophenyl)pyrazolo[3,4-d]pyrimidin-4-ones.
Burch, U.S. Pat. No. 3,350,397, issued Oct. 31, 1967, discloses as antibacterial agents pyrazolo[3,4-d]pyrimidines of formula: ##STR4## wherein: R represents a member of the group consisting of hydroxy, chloro and --N(X) (Y) wherein X represents a member of the group consisting of hydrogen, (lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl and amino; Y represents a member of the group consisting of hydrogen, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl and morpholinopropyl; X and Y taken together with N represent pyrrolidyl; and R.sup.1 represents a member of the group consisting of (lower)alkyl and methoxyethyl.
The patent further discloses, as intermediates, 4-amino and 4-hydroxy-1-R.sup.1 -6-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidines. The preparation of intermediates and the preparation and biological testing of final products is further exemplified by Burch in J. Med. Chem. 1968, 11, 79.
British Patent 937,722, published Sep. 25, 1963, to CIBA LIMITED, discloses as a coronary dilating agent 1-isopropyl-4-hydroxy-6-benzyl-pyrazolo[3,4-d]pyrimidine.
Hamilton, U.S. Pat. No. 4,666,908, issued May 19, 1987, discloses pyrazolo[4,3-d]pyrimidine-7-ones of formula: ##STR5## wherein: R.sup.1 is lower-alkyl of from one to six carbons, inclusive, lower-alkylene of from one to six carbon, inclusive, lower-hydroxyalkyl of from one to six carbons, inclusive, lower-hydroxyalkylene of from two to six carbons, inclusive, lower-aminoalkyl of from one to six carbons, inclusive, or lower-aminoalkylene of from two to six carbons, inclusive;
The patent more specifically discloses as preferred compounds those wherein Ar is R.sub.2. The compounds are stated to be useful in the treatment of cardiovascular disorders.
Miyashita et al., Heterocycles 1990, 31, 1309-1314, describe the preparation of a series of pyrazolo[3,4-d]pyrimidines of general formula: ##STR7## wherein: R is phenyl or methyl; and R.sup.1 is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, ethyl carboxylate or phenyl. No indication of utility is disclosed.
Hamilton, PCT Application WO 88/00192, published Jan. 14, 1988, discloses a series of 5-substituted pyrazolo[4,3-d]pyrimidin-7-one derivatives which are stated to be useful as cardiotonic, CNS stimulative, antiallergy, antiasthma or cognition activating agents.
Bell et al., European Patent Application 0463756, published Jan. 2, 1992, disclose a series of 5-(2,5-disubstituted-phenyl)pyrazolo[4,3-d]pyrimidin-7-ones which are stated to be useful in the treatment of cardiovascular disorders.
Breuer and Treuner, U.S. Pat. No. 3,847,908, issued Nov. 12, 1974, disclose compounds of the formula: ##STR8## wherein: R.sup.1 is lower-alkyl, cyclolower-alkyl, or phenyl-lower-alkyl;
Morrison et al., U.S. Pat. No. 4,260,758, issued Apr. 7, 1981, disclose the preparation of compounds of the formula: ##STR9## wherein R.sup.9 is selected from lower-alkyl, phenyl, phenyl substituted by one or more hydroxy or lower-alkoxy, or pyridyl. No utility is disclosed for the compounds.
Burch, Canadian Patent 754,565, issued Mar. 14, 1967, discloses a series of 4-substituted-1-alkyl-6-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidines which are said to be useful as intermediates in the preparation of 4-substituted-1-alkyl-6-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidines which are said to inhibit bacterial growth.
Podesva et al., U.S. Pat. No. 3,772,294, issued Nov. 13, 1973, disclose a process for preparing compounds of the formula I: ##STR10## wherein: X represents a halogen atom, a free or substituted hydroxyl, amino or mercapto group and R represents a hydrogen atom, or a lower-alkyl or a substituted or unsubstituted aryl radical. The compounds are disclosed as being potentially useful in the treatment of hyperuricemia associated with gout and other conditions and additionally, the compounds wherein X represents a halogen atom are said to be useful as intermediates in the synthesis of other compounds having the formula I. Specifically disclosed is 4-hydroxy-6-phenyl-1-pyrazolo[3,4-d]pyrimidine.
Coates and Rawlings, U.S. Pat. No. 5,075,310, issued Dec. 24, 1991 from application Ser. No. 370,494 filed Jun. 23, 1989, disclose and claim compounds of the formula: ##STR11## and pharmaceutically acceptable salts thereof, wherein: ##STR12## is a ring of sub-formula (a), (b) or (c): ##STR13## X is oxygen or sulphur; and R.sup.1 is C.sub.1 -C.sub.6 alkyl, C.sub.2-6 alkenyl, C.sub.3-5 cycloalkyl--C.sub.1-4 alkyl, or C.sub.1-4 alkyl substituted by 1 to 6 fluoro groups. Specifically disclosed is 6-(2-propoxyphenyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one. The compounds are said to be useful as bronchodilators and vasodilators.
Bacon et al, U.S. Pat. No. 5,294,612 issued Mar. 15, 1994 from Application Ser. No. 859,770 filed Mar. 30, 1992, discloses a series of 6-heterocyclyl-pyrazolo[3,4-d]pyrimidin-4-ones, e.g., 1-cyclopentyl-3-ethyl-6-(3-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one. The compounds are disclosed to be useful in treating heart failure and hypertension.